Ceramide is a potent signal transducer that affects cell growth, differentiation and death (Hannun, Y. A. (1996) Science 274, 1855-1859; Obeid, L. M., Linardic, C. M., Karolak, L. A., and Hannun, Y. A. (1993) Science 259, 1769-1771; Perry, D. K. and Hannun, Y. A., (1998) Biochim Biophys Acta 436, 233-243). It occupies a central position in sphingolipid metabolism. As an acceptor of carbohydrates, phosphorylcholine and phosphate, it serves as precursor of the various complex sphingolipids. Alternatively, the enzymatic breakdown of these sphingolipids releases ceramide which may consequently be hydrolyzed into fatty acid and sphingosine; the latter exerting effector functions on its own as well as acting as a precursor of sphingosine phosphate, another signal mediator and regulator of various cell functions. Ceramides are generated by hydrolysis of sphingomyelin in response to different stimuli, such as tumor necrosis factor, Fas/CD95 ligand, interleukin-1, and vitamin D3. A controlled level of ceramide, therefore, reflects an intricate balance between the catabolic and anabolic pathways of ceramide.
One of the most studied effects of ceramide is the ability to induce cell death. Endogenous ceramide levels are elevated in tumors after irradiation or therapy with anticancer drugs (Bose et al., Cell, 82:405-414, 1995; Selzner et al., Cancer Res. 61:1233-1240, 2001). Exogenous ceramides emerged as a promising new approach for cancer therapy. It has been shown that exogenous ceramide can induce cell death in a variety of cancer cell types with normal cells being less susceptible (von Haefen et al., Oncogene 21:4009-4019, 2002; Jones et al., Hepatology, 30:215-222, 1999).
Most studies of the effects of ceramides on cancer cells are restricted to the use of short-chain ceramides (C2-C8) because naturally occurring long-chain ceramides (C16-C24) are unable to penetrate cell membranes. Mitochondria have been identified as a target of ceramides. However, studies on the direct effect of ceramides on mitochondria are hampered by the fact that the ceramides are readily distributed to various organelles such as Golgi apparatus and endoplasmic reticulum (Radin, Bioorg Med Chem, 11:2123-2142, 2003; Ardail et al., Biochim Biophys Acta, 1583:305-310, 2002). Therefore, there is great interest in ceramides that can enter a cancer cell and target itself to the mitochondria where it induces cell death. The present invention provides a class of ceramide conjugates which have these desirable pharmacological properties making these conjugates suitable for development as therapeutic agents or drug delivery vehicles.
Citation of references hereinabove shall not be construed as an admission that such references are prior art to the present invention.